EP2307344B1 - Oxabicycloheptanes and oxabicycloheptenes, their preparation and use - Google Patents

Oxabicycloheptanes and oxabicycloheptenes, their preparation and use Download PDF

Info

Publication number
EP2307344B1
EP2307344B1 EP09803283.2A EP09803283A EP2307344B1 EP 2307344 B1 EP2307344 B1 EP 2307344B1 EP 09803283 A EP09803283 A EP 09803283A EP 2307344 B1 EP2307344 B1 EP 2307344B1
Authority
EP
European Patent Office
Prior art keywords
substituted
compound
alkyl
alkenyl
aryl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Not-in-force
Application number
EP09803283.2A
Other languages
German (de)
English (en)
French (fr)
Other versions
EP2307344A1 (en
EP2307344A4 (en
Inventor
John S. Kovach
Francis Johnson
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Lixte Biotechnology Inc
Original Assignee
Lixte Biotechnology Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Lixte Biotechnology Inc filed Critical Lixte Biotechnology Inc
Publication of EP2307344A1 publication Critical patent/EP2307344A1/en
Publication of EP2307344A4 publication Critical patent/EP2307344A4/en
Application granted granted Critical
Publication of EP2307344B1 publication Critical patent/EP2307344B1/en
Not-in-force legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • N-CoR Nuclear receptor co-repressor
  • the phosphatase inhibitor, Cantharidin has anti-tumor activity against human cancers of the liver (hepatomas) and of the upper gastrointestinal tract but is toxic to the urinary tract (Wang, 1989).
  • This invention discloses a process for preparing the above compound comprising (a) reacting compounds of the structure to form an anhydride the structure
  • This invention discloses a method of controlling undesired vegetation comprising contacting the vegetation or its environment with a herbicidally effective amount of the compounds of this invention.
  • This invention discloses a method of inhibiting plant phosphatase activity comprising contacting the plant or its environment with a herbicidally effective amount of the compounds of this invention.
  • the invention discloses a method of preventing or treating a fungal infection in a subject comprising administering to the subject an effective amount of the compounds of this invention.
  • This invention provides a compound of the invention for use in treating a subject with a neurodegenerative disease.
  • This invention discloses a method for reducing the amount of GSK-3 ⁇ in a cell comprising contacting the cell with an effective amount of any of the compounds of this invention so as to thereby reduce the amount of GSK-3 ⁇ in the cell.
  • This invention discloses a method for increasing the amount of phosphorylated Akt in a cell comprising contacting the neural cell with an effective amount of any of the compounds of this invention, so as to thereby increase the amount of phosphorylated Akt in the cell.
  • This invention discloses a method for reducing the phosphorylation of Tau in cell, comprising contacting the cell with an effective amount of any of the compounds of this invention, so as to thereby reduce the phosphorylation of Tau in the cell.
  • This invention discloses a method for reducing the aggregation of Tau in a cell, comprising contacting the cell with an effective amount of any of the compounds of this invention, so as to thereby reduce the phosphorylation of Tau in the cell.
  • the above compound has the structure
  • bond ⁇ is present. In another embodiment bond ⁇ is absent.
  • R 3 is O(CH 2 ) 1-6 R 9 or OR 10 , where R 9 is aryl or substituted ethyl; where R 10 is substituted phenyl, wherein the substituent is in the para position; R 4 is where X is O, S, NR 11 , or N + R 11 R 11 , where each R 11 is independently H, alkyl, hydroxyalkyl, substituted C 2 -C 12 alkyl, alkenyl, substituted C 4 -C 12 alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl where the substituent is other than chloro, -CH 2 CN, -CH 2 CO 2 R 12 , -CH 2 COR 12 , -NHR 12 or - NH + (R 12 ) 2 , where R 12 is alkyl, alkenyl or alkynyl, each of which is substituted or unsubstituted, or H; or where R 3 is
  • R 4 where R 11 is alkyl or hydroxylalkyl; or R 4 is when R 3 is OH.
  • R 1 and R 2 together O;
  • R 1 and R 2 together O;
  • R 7 and R 8 are each H.
  • R 3 is OR 10 , where R 10 is (-CH 2 ) 1 - 6 (CHNHBOC)CO 2 H, (CH 2 ) 1-6 (CHNH 2 )CO 2 H, or (CH 2 ) 1-6 CCl 3 .
  • R 10 is CH 2 (CHNHBOC)CO 2 H. In a further embodiment, R 10 is CH 2 CCl 3 .
  • R 3 is O(CH 2 ) 1-6 R 9 where R 9 is phenyl.
  • R 3 is O(CH 2 )R 9 where R9 is phenyl.
  • R 3 is OH and R 4 is
  • R 4 is wherein R 11 is hydroxyalkyl.
  • R 11 is-CH 2 CH 2 OH.
  • R 4 is wherein R 11 is alkyl. In further embodiment, R 11 is -CH3.
  • the compound has the structure
  • the compound has the structure
  • This invention provides a pharmaceutical composition comprising any of the above described compounds and a pharmaceutically acceptable carrier.
  • This invention discloses a process for preparing any of the above compounds comprising
  • the nuclephile comprises at least one hydroxyl group.
  • the nucleophile is O(CH 2 ) 1-6 R 9 or OR 10 , wherein Rg and R 10 are as described above.
  • the nucleophile comprises at least one free amine group. In a further embodiment the nucleophile is where X is as described herein.
  • the above process further comprises (c) reacting the product of step (b) with hydrogen in the presence of a catalyst to form a compound having the structure
  • the compounds disclosed hereinabove may be used in a method of controlling undesired vegetation comprising contacting the vegetation or its environment with a herbicidally effective amount of the compounds of any one of invention.
  • the compounds disclosed hereinabove may also be used in method of inhibiting plant phosphatase activity comprising contacting the plant or its environment with a herbicidally effective amount of the compounds of any one of the invention.
  • the compounds disclosed herein above may be used in a method of preventing or treating a fungal infection in a subject comprising administering to the subject an effective amount of the compounds of the invention to treat the fungal infection, thereby treating the fungal infection.
  • the compounds disclosed herein maybe used in a method of treating a subject afflicted with breast cancer, colon cancer, large cell lung cancer, adenocarcinoma of the lung, small cell lung cancer, stomach cancer, liver cancer, ovary adenocarcinoma, pancreas carcinoma, prostate carcinoma, promylocytic leukemia, chronic myelocytic leukemia, or acute lymphocytic leukemia, comprising administering to the subject a therapeutically effective amount of the compounds of the invention, thereby treating the subject.
  • the compounds disclosed herein may be used in a method of treating a subject with a neurodegenerative disease comprising administering to the subject an effective amount any of the compounds of the invention, thereby treating the subject.
  • the compounds disclosed herein may be used in a method for reducing the amount of GSK-3 ⁇ in a cell comprising contacting the cell with an effective amount of any of the compounds of the invention so as to thereby reduce the amount of GSK-3 ⁇ in the cell.
  • the compounds disclosed herein may be used in a method for increasing the amount of phosphorylated Akt in a cell comprising contacting the neural cell with an effective amount of any of the compounds of the invention, so as to thereby increase the amount of phosphorylated Akt in the cell.
  • the compounds disclosed herein may be used in a method for reducing the phosphorylation of Tau in cell, comprising contacting the cell with an effective amount of any of the compounds of the invention, so as to thereby reduce the phosphorylation of Tau in the cell.
  • the compounds disclosed herein may be used in a method for reducing the aggregation of Tau in a cell, comprising contacting the cell with an effective amount of any of the compounds of the invention, so as to thereby reduce the phosphorylation of Tau in the cell.
  • the compounds of the invention may also be used in a method of inhibiting proliferation of a cancer cell which does not overexpress N-CoR comprising administering to the subject any of the compounds of the invention in an amount to inhibit proliferation of the cancer cell.
  • the compounds of the invention may also be used in a method of inhibiting proliferation of a cancer cell which overexpresses TCTP comprising administering to the subject any of the compound of the invention in an amount effective to inhibit proliferation of the cancer cell.
  • the cancer may be adrenocortical cancer, bladder cancer, osteosarcoma, cervical cancer, esophageal, gallbladder, head and neck cancer, Hodgkin lymphoma, non-Hodgkin lymphoma, renal cancer, melanoma, pancreatic cancer, rectal cancer, thyroid cancer and throat cancer.
  • the histone deacetylase ligand may be an inhibitor, e.g. the histone deacetylase inhibitor of HDAC-3 (histone deacetylase-3).
  • the histone deacetylase ligand may also be selected from the group consisting of 2-amino-8-oxo-9,10-epoxy-decanoyl, 3-(4-aroyl-1H-pyrrol-2-yl)-N-hydroxy-2-propenamide, APHA Compound 8, apicidin, arginine butyrate, butyric acid, depsipeptide, depudecin, HDAC-3, m-carboxycinnamic acid bis-hydroxamide, N-(2-aminophenyl)-4-[N-(pyridin-3-ylmethoxycarbonyl) aminomethyl] benzamide, MS 275, oxamfiatin, phenylbutyrate, pyroxamide, scriptaid, sirtinol
  • the compounds of this invention may be used in combination with compounds which inhibit the enzyme histone deacetylase (HDAC).
  • HDAC histone deacetylase
  • Histones are groups of proteins which associate with DNA in eukaryotic cells to form compacted structures called chromatin. This compaction allows an enormous amount of DNA to be located within the nucleus of a eukaryotic cell, but the compact structure of chromatin restricts the access of transcription factors to the DNA. Acetylation of the histones decreases the compaction of the chromatin allowing transcription factors to bind to the DNA.
  • HDACs histone deacetylases
  • the invention further discloses the use of prodrugs which are converted in vivo to the compounds of the invention (see, e.g., R.B. Silverman, 1992, “The Organic Chemistry of Drug Design and Drug Action", Academic Press, Chapter 8 , the entire contents of which are hereby incorporated by reference).
  • prodrugs can be used to alter the biodistribution (e.g., to allow compounds which would not typically enter a reactive site) or the pharmacokinetics of the compound.
  • the compounds described in the present invention are in racemic form or as individual enantiomers.
  • the enantiomers can be separated using known techniques, such as those described, for example, in Pure and Applied Chemistry 69, 1469-1474, (1997 ) IUPAC.
  • zwitterion means a compound that is electrically neutral but carries formal positive and negative charges on different atoms. Zwitterions are polar, have high solubility in water and have poor solubility in most organic solvents.
  • the compounds disclosed herein may also form zwitterions.
  • a compound having the structure may also for the following zwitterionic structure where X is as defined throughout the disclosures herein.
  • solvent as used herein is intended to include compounds such as, hexanes, benzene, toluene, diethyl ether, chloroform, methylene chloride, ethyl acetate, 1,4-dioxane, water, THF, acetone, acetonitrile, DMF, DMSO, acetic acid, n-butanol, isopropanol, n-propanol, ethanol, methanol, formic acid, carbon tetrachloride, benzenethiol, chlorobenzene, cyclohexanethiol, 1-diethylaminoethanol, ethylene dichloride, ethylene glycol, xylene, 1,1,2,2-tetrachloroethane, phenol, acetic acid, 1-butanol, 2-butanol, 2-butanone, diglyme, dimethylether, dioxane, petroleum ether, (NMP) N-methyl
  • Certain embodiments of the disclosed compounds can contain a basic functional group, such as amino or alkylamino, and are thus capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable acids, or contain an acidic functional group and are thus capable of forming pharmaceutically acceptable salts with bases.
  • the instant compounds therefore may be in a salt form.
  • a "salt" is a salt of the instant compounds which has been modified by making acid or base salts of the compounds.
  • the salt may be pharmaceutically acceptable.
  • Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as phenols.
  • the salts can be made using an organic or inorganic acid.
  • Such acid salts are chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, formates, tartrates, maleates, malates, citrates, benzoates, salicylates, ascorbates, and the like.
  • Phenolate salts are the alkaline earth metal salts, sodium, potassium or lithium.
  • pharmaceutically acceptable salt in this respect, refers to the relatively non-toxic, inorganic and organic acid or base addition salts of compounds of the present invention.
  • salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or by separately reacting a purified compound of the invention in its free base or free acid form with a suitable organic or inorganic acid or base, and isolating the salt thus formed.
  • Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts and the like.
  • suitable salts see, e.g., Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66:1-19 .
  • terapéuticaally effective amount means an amount sufficient to treat a subject afflicted with a disease (e.g. cancer or a neurodegenerative disease) or to alleviate a symptom or a complication associated with the disease.
  • a disease e.g. cancer or a neurodegenerative disease
  • herbicidally effective means an amount sufficient to adversely affect plant growth, particularly through inhibition of plant phosphatase 2 A activity.
  • treating means slowing, stopping or reversing the progression of a disease, particularly cancer or a neurodegenerative disease.
  • a “neurodegenerative disease” refers to a disease in which degeneration occurs of either gray or white matter, or both, of the nervous system.
  • a disease can be diabetic neuropathy, senile dementias, Alzheimer's disease, Mild Cognitive Impairment (MCI), dementia, Lewy Body Dementia, Frontal Temporal Lobe dementia, Parkinson's Disease, facial nerve (Bell's) palsy, glaucoma, Huntington's chorea, amyotrophic lateral sclerosis (ALS), status epilepticus, non-arteritic optic neuropathy, intervertebral disc herniation, vitamin deficiency, prion diseases such as Creutzfeldt-Jakob disease, carpal tunnel syndrome, peripheral neuropathies associated with various diseases, including but not limited to, uremia, porphyria, hypoglycemia, Sjorgren Larsson syndrome, acute sensory neuropathy, chronic ataxic neuropathy, biliary cirrhosis, primary amy
  • tauopathies refers to a class of neurodegenerative diseases which result from aggregation of tau protein in neurofibrillary tangles.
  • tauopathies include, but are not limited to, Alzheimer's disease, Frontotemporal dementia (Pick's disease), Progressive Supranuclear Palsy, and Corticobasal degeneration.
  • alkyl is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms.
  • C 1 -C n as in “C 1 -C n alkyl” is defined to include groups having 1, 2, ...., n-1 or n carbons in a linear or branched arrangement, and specifically includes methyl, ethyl, propyl, butyl, pentyl, hexyl, and so on.
  • An embodiment can be C 1 -C 12 alkyl.
  • Alkoxy represents an alkyl group as described above attached through an oxygen bridge.
  • Hydroxyl represents an alkyl group as described aboved with a hydroxyl group. Hydroxyalky groups include, for example, (CH 2 ) 1-10 OH and includes CH 2 OH, CH 2 CH 2 OH, CH 2 CH 2 CH 2 OH and so forth.
  • alkenyl refers to a non-aromatic hydrocarbon radical, straight or branched, containing at least 1 carbon to carbon double bond, and up to the maximum possible number of non-aromatic carbon-carbon double bonds may be present.
  • C 2 -C n alkenyl is defined to include groups having 2, 3, ...., n-1 or n carbons.
  • C 2 -C 6 alkenyl means an alkenyl radical having 2, 3, 4, 5, or 6 carbon atoms, and at least 1 carbon-carbon double bond, and up to, for example, 3 carbon-carbon double bonds in the case of a C 6 , alkenyl, respectively.
  • Alkenyl groups include ethenyl, propenyl, butenyl and cyclohexenyl. As described above with respect to alkyl, the straight, branched or cyclic portion of the alkenyl group may contain double bonds and may be substituted if a substituted alkenyl group is indicated. An embodiment can be C 2 -C 12 alkenyl.
  • alkynyl refers to a hydrocarbon radical straight or branched, containing at least 1 carbon to carbon triple bond, and up to the maximum possible number of non-aromatic carbon-carbon triple bonds may be present.
  • C 2 -C n alkynyl is defined to include groups having 2, 3, ...., n-1 or n carbons.
  • C 2 -C 6 alkynyl means an alkynyl radical having 2 or 3 carbon atoms, and 1 carbon-carbon triple bond, or having 4 or 5 carbon atoms, and up to 2 carbon-carbon triple bonds, or having 6 carbon atoms, and up to 3 carbon-carbon triple bonds.
  • Alkynyl groups include ethynyl, propynyl and butynyl. As described above with respect to alkyl, the straight or branched portion of the alkynyl group may contain triple bonds and may be substituted if a substituted alkynyl group is indicated. An embodiment can be a C 2 -C n alkynyl.
  • aryl is intended to mean any stable monocyclic or bicyclic carbon ring of up to 10 atoms in each ring, wherein at least one ring is aromatic.
  • aryl elements include phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthryl or acenaphthyl.
  • the aryl substituent is bicyclic and one ring is non-aromatic, it is understood that attachment is via the aromatic ring.
  • the substituted aryls included in this invention include substitution at any suitable position with amines, substituted amines, alkylamines, hydroxys and alkylhydroxys, wherein the "alkyl" portion of the alkylamines and alkylhydroxys is a C 2 -C n alkyl as defined hereinabove.
  • the substituted amines may be substituted with alkyl, alkenyl, alkynl, or aryl groups as hereinabove defined.
  • alkyl, alkenyl, alkynyl, and aryl substituents may be substituted or unsubstituted, unless specifically defined otherwise.
  • a (C 1 -C 6 ) alkyl may be substituted with one or more substituents selected from OH, oxo, halogen, which includes F, Cl, Br, and I, alkoxy, dialkylamino, or heterocyclyl, such as morpholinyl, piperidinyl, and so on.
  • alkyl, alkenyl, and alkynyl groups can be further substituted by replacing one or more hydrogen atoms by non-hydrogen groups described herein to the extent possible.
  • non-hydrogen groups include, but are not limited to, halo, hydroxy, mercapto, amino, carboxy, cyano and carbamoyl.
  • substituted means that a given structure has a substituent which can be an alkyl, alkenyl, or aryl group as defined above.
  • the term shall be deemed to include multiple degrees of substitution by a named substitutent.
  • the substituted compound can be independently substituted by one or more of the disclosed or claimed substituent moieties, singly or plurally.
  • independently substituted it is meant that the (two or more) substituents can be the same or different.
  • administering an agent may be performed using any of the various methods or delivery systems well known to those skilled in the art.
  • the administering can be performed, for example, orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via inhalation, vaginally, intraoccularly, via local delivery, subcutaneously, intraadiposally, intraarticularly, intrathecally, into a cerebral ventricle, intraventicularly, intratumorally, into cerebral parenchyma or intraparenchchymally.
  • compositions in accordance with the invention may be used but are only representative of the many possible systems envisioned for administering compositions in accordance with the invention.
  • Injectable drug delivery systems include solutions, suspensions, gels, microspheres and polymeric injectables, and can comprise excipients such as solubility-altering agents (e.g., ethanol, propylene glycol and sucrose) and polymers (e.g., polycaprylactones and PLGA's).
  • solubility-altering agents e.g., ethanol, propylene glycol and sucrose
  • polymers e.g., polycaprylactones and PLGA's.
  • Implantable systems include rods and discs, and can contain excipients such as PLGA and polycaprylactone.
  • Oral delivery systems include tablets and capsules. These can contain excipients such as binders (e.g., hydroxypropylmethylcellulose, polyvinyl pyrilodone, other cellulosic materials and starch), diluents (e.g., lactose and other sugars, starch, dicalcium phosphate and cellulosic materials), disintegrating agents (e.g., starch polymers and cellulosic materials) and lubricating agents (e.g., stearates and talc).
  • excipients such as binders (e.g., hydroxypropylmethylcellulose, polyvinyl pyrilodone, other cellulosic materials and starch), diluents (e.g., lactose and other sugars, starch, dicalcium phosphate and cellulosic materials), disintegrating agents (e.g., starch polymers and cellulosic materials) and lubricating agents (e.
  • Transmucosal delivery systems include patches, tablets, suppositories, pessaries, gels and creams, and can contain excipients such as solubilizers and enhancers (e.g., propylene glycol, bile salts and amino acids), and other vehicles (e.g., polyethylene glycol, fatty acid esters and derivatives, and hydrophilic polymers such as hydroxypropylmethylcellulose and hyaluronic acid).
  • solubilizers and enhancers e.g., propylene glycol, bile salts and amino acids
  • other vehicles e.g., polyethylene glycol, fatty acid esters and derivatives, and hydrophilic polymers such as hydroxypropylmethylcellulose and hyaluronic acid.
  • Dermal delivery systems include, for example, aqueous and nonaqueous gels, creams, multiple emulsions, microemulsions, liposomes, ointments, aqueous and nonaqueous solutions, lotions, aerosols, hydrocarbon bases and powders, and can contain excipients such as solubilizers, permeation enhancers (e.g., fatty acids, fatty acid esters, fatty alcohols and amino acids), and hydrophilic polymers (e.g., polycarbophil and polyvinylpyrolidone).
  • the pharmaceutically acceptable carrier is a liposome or a transdermal enhancer.
  • Solutions, suspensions and powders for reconstitutable delivery systems include vehicles such as suspending agents (e.g., gums, xanthans, cellulosics and sugars), humectants (e.g., sorbitol), solubilizers (e.g., ethanol, water, PEG and propylene glycol), surfactants (e.g., sodium lauryl sulfate, Spans, Tweens, and cetyl pyridine), preservatives and antioxidants (e.g., parabens, vitamins E and C, and ascorbic acid), anti-caking agents, coating agents, and chelating agents (e.g., EDTA).
  • suspending agents e.g., gums, xanthans, cellulosics and sugars
  • humectants e.g., sorbitol
  • solubilizers e.g., ethanol, water, PEG and propylene glycol
  • substituents and substitution patterns on the compounds of the instant invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art, as well as those methods set forth below, from readily available starting materials. If a substituent is itself substituted with more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons, so long as a stable structure results.
  • Cantharidin has anti-tumor activity against human cancers of the liver (hepatomas) and of the upper gastrointestinal tract but is toxic to the urinary tract (Wang, 1989).
  • Norcantharidin a demethylated cantharidin, maintains antitumor activity of cantharidin against hepatomas and cancers of the stomach and esophagus, but has little or no urinary tract toxicity.
  • Norcantharidin also stimulates white blood cell production in patients and mice, a phenomenon not understood mechanistically, but a pharmacological effect of potential benefit as an anticancer agent (Wang et al ., 1986; Wang, 1989).
  • cantharidin analogues had been previously synthesized and evaluated as pesticides and for antitumor activity against cancer cell lines. Forty-three analogues of endothal and cantharidin have been developed and assessed for their activity as herbicides and their lethality to mice (Matsuzawa et al., 1987). Endothal thioanhydride was shown to be a more potent herbicide than endothal but was toxic to the liver of mice (Matsuzawa et al., 1987; Kawamura et al., 1990).
  • endothal thioanhydride is an active agent against PP2A and PP1 in vivo (Erdodi et al., 1995). Endothal and endothal thioanhydride, like cantharidin, inhibit the activity of PP2A and to some extent, the activity of PP1 (Erdodi et al., 1995). In the liver, the principal target appears to be PP1. In fibroblasts, only endothal thioanhydride caused marked morphological changes whereas cantharidin and endothal did not (Erdodi et al., 1995).
  • endothal thioanhydride in vivo is thought to be related to its enhanced lipophilicity resulting in increased diffusion across the plasmalemma (Essers et al., 2001).
  • a more recent publication has described the synthesis of the mono-, and the di-fluoro analogues of Endothal and also the corresponding anhydrides, however no pharmacological data accompanied this synthetic work (Essers et al., 2001).
  • the compounds described herein have an antagonistic effect on phosphatase-2A and phosphatase 1.
  • compounds 110, 112, 113 and 114 each have properties that enhance their entry into the brain.
  • Endothal is also known as an active defoliant and potent contact herbicide used in many agricultural situations. It is considered effective as a pre-harvest desiccant and as a selective pre-emergence herbicide (Crafts, 1953).
  • Endothal, norcantharidins and cantharidin are all well known inhibitors of mammalian protein phosphatase as well as potent herbicides (Matsuzawa et al ., 1987).
  • the mechanism by which endothal and other homologs exert their potent herbicidal activity has not been studied extensively despite the widespread use of endothal internationally in agriculture. It should be noted that endothal is water soluble where cantharidin and norcantharidin are not.
  • endothal As a contact herbicide and defoliant is related to the known irritating toxicity of its parent compound, norcantharidin.
  • the herbicidal activity of endothal may be a function primarily of its anti-plant protein phosphatase (PP2A) activity.
  • PP2A anti-plant protein phosphatase
  • Li et al. (1993) showed that cantharidin and endothal inhibit spinach leaf PP2A and PP1 and inhibit the activation of nitrate reductase by light in the intact spinach leaf, a process mediated by PP2A. Smith et al.
  • Baskin and Wilson showed inhibitors of serine-threonine protein phosphatases including cantharidin inhibit organization of plant microtubules.
  • Ayaydin et al. (2000) show that endothal inhibited PP2A activity causing alteration of cell division in cultured alfalfa cells. They noted that endothal was cell permeable.
  • the compounds herein, therefore, are useful, commercially feasible, and safer herbicides both with respect human exposure and to the environment.
  • the compounds disclosed herein are also useful for the treatment of tumors.
  • the compounds are useful for the treatment of tumors which overexpress N-CoR, TCTP, or both.
  • the compounds disclosed herein are also useful for the treatment of fungal infections.
  • the compounds are useful for the treatment of a fungal infections of T. rubrum.
  • the human medulloblastoma cell line DAOY is available from the American Type Culture Collection (ATCC), P.O. Box 1549, Manassa, Virginia, 20108, as ATCC No. HTB-186.
  • Step 1 Synthesis of 7-oxa-bicyclo[2.2.1]heptane-2,3-dicarboxylic acid monobenzyl ester (10):
  • Step 2 3-[4-(2-Hydroxyethyl)-piperazine-1-carbonyl]-7-oxa-bicyclo[2.2.1] heptane-2-carboxylic acid benzyl ester (12, Compound 109):
  • Step 1 3- (4-Methylpiperazine-1-carbonyl)-7-oxa-bicyclo[2,2,1]heptane-2-carbonyl chloride (1):
  • Step 2 3-(4-Methylpiperazine-l-carbonyl)-7-oxa-bicyclo
  • reaction mixture was diluted with methylene chloride (30 mL) and washed with water (30 mL) followed by brine, dried over anhydrous sodium sulfate, filtered and concentrated.
  • the crude residue was purified by column chromatography using 5% methanol in methylene chloride to give pure required compound 3 (1.040 g, 76%).
  • Step 3 3-(4-Methylpiperazine-1-carbonyl)-7-oxa-bicyclo[2,2,1] heptane-2-carboxylic acid 4-(2-tert-butoxycarbonylamlno-2-carboxyethyl)-phenyl ester (4, Compound 112):
  • Example 2 Inhibition of growth of glioblastoma multiforme cells of line U373 by exposure for 7 days to increasing concentrations of compound 109, 110, 112, and 113
  • the compounds described herein increase the phosphorylation of several regulatory proteins including Akt. At low doses that are non-toxic to mice, these compounds slightly stimulate cell proliferation and increase phosphorylation of Akt in human cancer cells lines tested, including SH-SY5Y. When given intraperitoneally to normal mice, compounds 110, 113 and 114 also increased Akt phosphorylation in the cell lines tested, as set forth in the examples herein.
  • the compounds increase cellular Akt at low non-toxic doses and also increase acetylation of histones in neurons of the intact animal, these compounds are useful for the treatment of neurodegenerative diseases, particulary Alzheimer's disease and other tauopathies. While each of the compounds increase Akt phosphorylation of multiple tumor cell lines, they also increase Akt phosphorylation of the neuroblastoma cell line SH-SY5Y.
  • the mechanism by which the compounds described herein exert their neuroprotective effect may be by increasing the intra-neuronal cell activity of Akt-1 and enhancing the acetylation of neuronal histones.
  • Akt-1 intra-neuronal cell activity
  • enhancing the acetylation of neuronal histones Each of these compounds when given by intraperitoneal injection increase Akt phosphorylation in mouse neurons. This increase in Akt phosphorylation is associated with an increase in the phosphorylation of GSK-3 ⁇ . Because increased phosphorylation of GSK-3 ⁇ is known to decrease its activity, chronic suppression of GSK 3 ⁇ by the compounds described herein may reduce tau phosphorylation.
  • Reduction in tau phosphorylation reduces the formation of paired helical filaments, an intervention that should lessen the progression of tauopathies, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and other rarer neurodegenerative diseases characterized by abnormal depositions of tau molecules.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Oncology (AREA)
  • Hospice & Palliative Care (AREA)
  • Hematology (AREA)
  • Psychiatry (AREA)
  • Communicable Diseases (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)
EP09803283.2A 2008-08-01 2009-07-30 Oxabicycloheptanes and oxabicycloheptenes, their preparation and use Not-in-force EP2307344B1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US13769108P 2008-08-01 2008-08-01
PCT/US2009/004430 WO2010014254A1 (en) 2008-08-01 2009-07-30 Oxabicycloheptanes and oxabicycloheptenes, their preparation and use

Publications (3)

Publication Number Publication Date
EP2307344A1 EP2307344A1 (en) 2011-04-13
EP2307344A4 EP2307344A4 (en) 2012-05-02
EP2307344B1 true EP2307344B1 (en) 2015-07-29

Family

ID=41608964

Family Applications (1)

Application Number Title Priority Date Filing Date
EP09803283.2A Not-in-force EP2307344B1 (en) 2008-08-01 2009-07-30 Oxabicycloheptanes and oxabicycloheptenes, their preparation and use

Country Status (11)

Country Link
US (2) US8227473B2 (ru)
EP (1) EP2307344B1 (ru)
JP (2) JP5666443B2 (ru)
CN (1) CN102333752A (ru)
AU (1) AU2009277031B2 (ru)
BR (1) BRPI0911717A2 (ru)
CA (1) CA2730489C (ru)
EA (1) EA022311B1 (ru)
HK (1) HK1151791A1 (ru)
MX (1) MX2011001007A (ru)
WO (1) WO2010014254A1 (ru)

Families Citing this family (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090018142A9 (en) * 2006-05-02 2009-01-15 Zhengping Zhuang Use of phosphatases to treat tumors overexpressing N-CoR
WO2008097561A1 (en) 2007-02-06 2008-08-14 Lixte Biotechology Holdings, Inc. Oxabicycloheptanes and oxabicycloheptenes, their preparation and use
CN101854804B (zh) 2007-10-01 2014-07-23 利克斯特生物技术公司 Hdac抑制剂
US8227473B2 (en) * 2008-08-01 2012-07-24 Lixte Biotechnology, Inc. Oxabicycloheptanes and oxabicycloheptenes, their preparation and use
CA2730428A1 (en) * 2008-08-01 2010-02-04 Lixte Biotechnology, Inc. Methods for regulating cell mitosis by inhibiting serine/threonine phosphatase
WO2010147612A1 (en) 2009-06-18 2010-12-23 Lixte Biotechnology, Inc. Methods of modulating cell regulation by inhibiting p53
CA2730148C (en) * 2008-08-01 2018-04-03 Lixte Biotechnology, Inc. Neuroprotective agents for the prevention and treatment of neurodegenerative diseases
WO2012064898A1 (en) * 2010-11-09 2012-05-18 Yuan Chen Singleton inhibitors of sumoylation enzymes and methods for their use
AU2013282365A1 (en) 2012-06-29 2015-02-19 Lixte Biotechnology, Inc. Oxabicycloheptanes and oxabicycloheptenes for the treatment of diabetes
CA2909160C (en) 2013-04-09 2021-05-25 Lixte Biotechnology, Inc. Formulations of oxabicycloheptanes and oxabicycloheptenes
JP2016538281A (ja) * 2013-11-15 2016-12-08 リクスト・バイオテクノロジー，インコーポレイテッド 血液脳関門を通過するタンパク質ホスファターゼ阻害剤
TN2016000441A1 (en) 2014-05-13 2018-04-04 Novartis Ag Compounds and compositions for inducing chondrogenesis.
CN106572989B (zh) 2014-07-24 2021-08-27 H·李·莫菲特癌症中心与研究所公司 用于治疗骨髓增生异常综合征的蛋白磷酸酶2a抑制剂
US9833450B2 (en) 2015-02-19 2017-12-05 Lixte Biotechnology, Inc. Oxabicycloheptanes and oxabicycloheptenes for the treatment of depressive and stress disorders
DK3294287T3 (da) 2015-05-15 2020-06-08 Lixte Biotechnology Inc Oxabicycloheptan-prodrugs
IL290857B2 (en) 2016-12-08 2023-03-01 Lixte Biotechnology Inc Oxabicycloheptanes for immune response modulation
CN111303179B (zh) * 2020-03-17 2022-12-02 遵义医科大学 一类去甲斑蝥素羧酸二氟苄酯的合成及其抗肿瘤应用
CN116531361A (zh) * 2022-12-01 2023-08-04 武汉大学 氧桥双环-[2.2.1]-庚烯类化合物在制备抗新型冠状病毒药物中的应用

Family Cites Families (109)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2957906A (en) 1955-10-25 1960-10-25 Monsanto Chemicals Ketones
US3022268A (en) 1958-07-17 1962-02-20 Du Pont Polyethylene composition
JPS5752354B2 (ru) * 1973-10-22 1982-11-06
US3980674A (en) * 1974-01-28 1976-09-14 Delmar Chemicals Limited 2,3-Disubstituted 7-oxabicyclo-[2.2.1]-5-heptene
US3954913A (en) * 1975-01-06 1976-05-04 The Standard Oil Company Stabilized nitrile polymers
JPS5188631A (en) 1975-01-31 1976-08-03 Hiiryoyosatsukinzai oyobi sonoseizoho
US4143054A (en) 1977-11-04 1979-03-06 E. R. Squibb & Sons, Inc. 7-oxabicycloheptane- and 7-oxabicycloheptene compounds
US4218478A (en) 1979-01-05 1980-08-19 Ruiko Oiwa Trichostatin as an antiprotozoal agent
US4298752A (en) 1980-09-19 1981-11-03 Regents Of The University Of California Cycloadduct precursors of cantharidin and method
US4410681A (en) 1982-03-22 1983-10-18 The Dow Chemical Company Epoxy resins cured with salicyloyl hydrocarbylamines
US4614825A (en) 1982-05-17 1986-09-30 E. R. Squibb & Sons, Inc. 7-oxabicycloheptane and 7-oxabicycloheptene compounds
US4463015A (en) 1982-08-18 1984-07-31 E. R. Squibb & Sons, Inc. Aryl substituted 7-oxabicycloheptane compounds, useful in inhibiting platelet aggregation
US4524151A (en) 1983-11-14 1985-06-18 E. R. Squibb & Sons, Inc. 7-Oxabicycloheptane thio ethers useful as cardiovascular agents
JPS61176523A (ja) 1985-01-30 1986-08-08 Teruhiko Beppu 制癌剤
US4654355A (en) 1985-08-01 1987-03-31 E. R. Squibb & Sons, Inc. 7-oxabicycloheptane substituted amide-thioamide prostaglandin analogs
US4851553A (en) 1986-06-04 1989-07-25 E. R. Squibb & Sons, Inc. 7-oxabicycloheptane amido-carboxylic acids
US4816579A (en) 1986-06-04 1989-03-28 E. R. Squibb & Sons, Inc. 7-oxabicycloheptane amino-alcohol intermediates useful in making thromboxane A2 receptor antagonists
US4851423A (en) 1986-12-10 1989-07-25 Schering Corporation Pharmaceutically active compounds
SU1553533A1 (ru) 1988-01-28 1990-03-30 Военная Краснознаменная академия химической защиты им.Маршала Советского Союза С.К.Тимошенко Способ получени 1,4-бисполифторалкил-7-оксбицикло [2.2.1]гептанов
US5047574A (en) * 1988-12-14 1991-09-10 Shionogi & Co., Ltd. Certain optically active mono esters of dicarboxylic acids
RU2015980C1 (ru) * 1990-02-06 1994-07-15 Е.Р.Сквибб энд Санз, Инк. 7-оксабициклогептилзамещенные гетероциклические амиды или их стереоизомеры в качестве антагонистов рецепторов тромбоксана
US5763647A (en) 1990-03-30 1998-06-09 Shionogi & Co., Ltd. Preparation of optically active 1,4-bridged-cyclohexane carboxylic acid derivatives
US5266710A (en) 1990-12-18 1993-11-30 Patel Ramesh N (Exo,exo)-7-oxabicyclo[2.2.1]heptane-2,3-dimethanol; monoacyl ester and diacyl ester
US5326898A (en) 1992-02-11 1994-07-05 Allergan, Inc. Substituted phenylethenyl compounds having retinoid-like biological activity
US6602713B1 (en) 2001-02-09 2003-08-05 Isis Pharmaceuticals, Inc. Antisense modulation of protein phosphatase 2 catalytic subunit beta expression
US5518993A (en) 1994-08-12 1996-05-21 Buckman Laboratories International, Inc. Pesticidal compositions containing ethoxylated fatty amines for increasing the effectiveness of endothal and salts thereof
US5770382A (en) 1994-12-30 1998-06-23 Ligand Pharmaceuticals, Inc. Tricyclic retinoids, methods for their production and use
US6222055B1 (en) 1995-07-06 2001-04-24 Fraunhofer-Gesellschaft Zur Foerderung Der Angwandten Forschung E.V. Hydrolyzable and polymerizable and/or polyadditive silanes
DE19600707B4 (de) 1996-01-11 2004-02-19 Glüsenkamp, Karl-Heinz, Dr. Biyclische Anhydrid-Wirkstoff-Verbindungen, Verfahren zur Herstellung und Verwendung derselben
US5968965A (en) 1996-01-30 1999-10-19 Merck & Co., Inc. Inhibitors of farnesyl-protein transferase
US6777217B1 (en) 1996-03-26 2004-08-17 President And Fellows Of Harvard College Histone deacetylases, and uses related thereto
US5925651A (en) 1996-04-03 1999-07-20 Merck & Co., Inc. Inhibitors of farnesyl-protein transferase
US6387673B1 (en) 1997-05-01 2002-05-14 The Salk Institute For Biological Studies Compounds useful for the modulation of processes mediated by nuclear hormone receptors, methods for the identification and use of such compounds
PT1621077E (pt) 1997-10-15 2008-11-04 Polarx Biopharmaceuticals Inc Composições farmacêuticas compreendendo trióxido de arsénico para o tratamento de um tumor do sistema nervoso central
US6632823B1 (en) 1997-12-22 2003-10-14 Merck & Co., Inc. Substituted pyridine compounds useful as modulators of acetylcholine receptors
AU762626B2 (en) 1998-06-05 2003-07-03 Nutrinia Ltd Insulin supplemented infant formula
AUPP466598A0 (en) 1998-07-14 1998-08-06 University Of Newcastle Research Associates Limited, The Product and process
US20040110822A1 (en) 1998-07-14 2004-06-10 The University Of Newcastle Research Associates Anhydride modified cantharidin analogues useful in the treatment of cancer
ATE329911T1 (de) 1998-08-07 2006-07-15 Applied Research Systems Fsh mimetika zur behandlung von infertilität
US20020151515A1 (en) 1999-06-18 2002-10-17 Roberts Bruce L. Preparation and use of superior vaccines
US6949624B1 (en) 1999-08-03 2005-09-27 The United States Of America As Represented By The Department Of Health And Human Services Cloning of the human nuclear receptor co-repressor gene
EA007649B1 (ru) 1999-09-08 2006-12-29 Слоан-Кеттеринг Инститьют Фор Кэнсер Рисёч Ингибиторы гистондеацетилазы, вызывающие дифференцировку клеток, и их применение
US7605185B2 (en) 1999-11-23 2009-10-20 Gerhart Graupner Treatment of arrhythmia by retinoids affecting signal transduction
JP4518627B2 (ja) 2000-03-14 2010-08-04 旭化成イーマテリアルズ株式会社 ヒドロキシポリアミド
AU2001248701A1 (en) 2000-03-24 2001-10-03 Methylgene, Inc. Inhibitors of histone deacetylase
PE20020354A1 (es) 2000-09-01 2002-06-12 Novartis Ag Compuestos de hidroxamato como inhibidores de histona-desacetilasa (hda)
DE60112312T2 (de) 2000-09-21 2005-12-29 Smithkline Beecham P.L.C., Brentford Imidazolderivate als raf-kinase-inhibitoren
US6696483B2 (en) 2000-10-03 2004-02-24 Oncopharmaceutical, Inc. Inhibitors of angiogenesis and tumor growth for local and systemic administration
CN1213050C (zh) * 2000-11-23 2005-08-03 拜尔公司 氧杂双环[2.2.1]庚烷衍生物，其制备方法和作为农药的用途
US20020177692A1 (en) 2001-04-16 2002-11-28 Myriad Genetics, Incorporated BCL-XL-interacting protein and use thereof
AUPR392301A0 (en) 2001-03-23 2001-04-26 University Of Newcastle Research Associates Limited, The Protein phosphatase inhibitors
US20040253637A1 (en) 2001-04-13 2004-12-16 Biosite Incorporated Markers for differential diagnosis and methods of use thereof
US6905669B2 (en) 2001-04-24 2005-06-14 Supergen, Inc. Compositions and methods for reestablishing gene transcription through inhibition of DNA methylation and histone deacetylase
US20070015144A9 (en) 2001-05-25 2007-01-18 Genset, S.A. Human cDNAs and proteins and uses thereof
WO2003014062A1 (en) 2001-08-03 2003-02-20 The Government Of The United States As Represented By The Secretary Of The Department Of Health And Human Services Acylthiols and component thiol compositions as anti-hiv and anti-retroviral agents
US20040010045A1 (en) 2001-09-07 2004-01-15 Taolin Yi Therapeutic compositions comprised of pentamidine and methods of using same to treat cancer
US7179450B2 (en) * 2001-09-20 2007-02-20 Medi-Physics, Inc. Methods for in vivo evaluation of pulmonary physiology and/or function using NMR signals of polarized Xe
US20040087657A1 (en) 2001-10-16 2004-05-06 Richon Victoria M. Treatment of neurodegenerative diseases and cancer of the brain using histone deacetylase inhibitors
CN100457183C (zh) 2001-11-06 2009-02-04 诺瓦提斯公司 环氧酶-2抑制剂/组蛋白脱乙酰酶抑制剂的组合
US7488712B2 (en) 2002-02-20 2009-02-10 Kyushu Institute Of Technology Histone deacetylase inhibitors and methods for producing the same
US7456219B2 (en) 2002-03-04 2008-11-25 Merck Hdac Research, Llc Polymorphs of suberoylanilide hydroxamic acid
US7148257B2 (en) 2002-03-04 2006-12-12 Merck Hdac Research, Llc Methods of treating mesothelioma with suberoylanilide hydroxamic acid
EA013643B1 (ru) 2002-03-08 2010-06-30 Басф Акциенгезельшафт Фунгицидная смесь на базе протиоконазола с тиаметоксамом
US6809118B2 (en) 2002-07-25 2004-10-26 Yih-Lin Chung Methods for therapy of radiation cutaneous syndrome
WO2003092616A2 (en) 2002-05-01 2003-11-13 The Cleveland Clinic Foundation Therapeutic compositions comprised of pentamidine and methods of using same to treat cancer
KR20060010709A (ko) 2002-09-23 2006-02-02 쉐링 코포레이션 사이클린 의존성 키나제 억제제로서의 신규한 이미다조피라진
US7154002B1 (en) 2002-10-08 2006-12-26 Takeda San Diego, Inc. Histone deacetylase inhibitors
ES2245619T1 (es) 2002-11-05 2006-01-16 The Regents Of The University Of California Procedimientos y materiales para examinar vias asociadas a la progresion de glioblastoma.
GB0226855D0 (en) 2002-11-18 2002-12-24 Queen Mary & Westfield College Histone deacetylase inhibitors
US20040197888A1 (en) 2002-12-31 2004-10-07 Armour Christopher D. Alternatively spliced isoforms of histone deacetylase 3 (HDAC3)
US20050222013A1 (en) 2003-01-16 2005-10-06 Georgetown University Methods for the use of inhibitors of histone deacetylase as synergistic agents in cancer therapy
CA2518407A1 (en) 2003-03-12 2004-09-23 Samaritan Pharmaceuticals, Inc. Animal model simulating neurologic disease
US7842835B2 (en) 2003-07-07 2010-11-30 Georgetown University Histone deacetylase inhibitors and methods of use thereof
JP2007502287A (ja) 2003-08-13 2007-02-08 アムジェン インコーポレイテッド メラニン凝集ホルモン受容体アンタゴニスト
US20050203082A1 (en) 2003-08-13 2005-09-15 Hsu Chung Y. Combination therapy with inhibitors of inducible nitric oxide synthase and alkylating agents
US7378409B2 (en) 2003-08-21 2008-05-27 Bristol-Myers Squibb Company Substituted cycloalkylamine derivatives as modulators of chemokine receptor activity
WO2005018673A1 (en) 2003-08-21 2005-03-03 Osaka University Pharmaceutical composition for preventing or remedying cardiac hypertrophy and cardiocascular disease caused thereby
US7094193B2 (en) 2003-08-28 2006-08-22 Philip Morris Usa Inc. High speed laser perforation of cigarette tipping paper
US20070004771A1 (en) 2003-10-06 2007-01-04 Glaxo Group Limited Preparation of 1,6,7-trisubstituted azabenzimidazoles as kinase inhibitors
US20070208166A1 (en) 2003-10-24 2007-09-06 Exelixis, Inc. Tao Kinase Modulators And Method Of Use
AU2004291102A1 (en) 2003-11-13 2005-06-02 Board Of Regents, The University Of Texas System Inhibition of TRP channels as a treatment for cardiac hypertrophy and heart failure
GB0328157D0 (en) 2003-12-04 2004-01-07 Imp College Innovations Ltd Compounds
EP1699436A2 (en) 2003-12-12 2006-09-13 Myogen, Inc. Enoximone formulations and their use in the treatment of cardiac hypertrophy and heart failure
US8652502B2 (en) 2003-12-19 2014-02-18 Cordis Corporation Local vascular delivery of trichostatin A alone or in combination with sirolimus to prevent restenosis following vascular injury
US20050282893A1 (en) 2004-01-30 2005-12-22 Au Jessie L Methods and compositions for using suramin, pentosan, polysulfate, telomerase antisense and telomerase inhibitors
CA2555632A1 (en) 2004-02-02 2005-08-18 Myogen, Inc. Inhibition of protein kinase c-related kinase (prk) as a treatment for cardiac hypertrophy and heart failure
US7253204B2 (en) 2004-03-26 2007-08-07 Methylgene Inc. Inhibitors of histone deacetylase
US8299083B2 (en) 2004-08-17 2012-10-30 The Johns Hopkins University PDE5 inhibitor compositions and methods for treating cardiac indications
KR100677149B1 (ko) 2004-11-12 2007-02-02 삼성전자주식회사 잉크 조성물
EP1863804A1 (en) 2005-04-01 2007-12-12 Methylgene, Inc. Inhibitors of histone deacetylase
GB0511266D0 (en) 2005-06-02 2005-07-13 Trust Chemical compounds
US20090220507A1 (en) 2005-07-22 2009-09-03 Sucharov Carmen C Inhibition of extracellular signal-regulated kinase 1/2 as a treatment for cardiac hypertrophy and heart failure
CN101282718A (zh) 2005-08-10 2008-10-08 诺瓦提斯公司 脱乙酰酶抑制剂的使用方法
EP1963258A4 (en) 2005-12-19 2011-06-29 Methylgene Inc HISTONE DEACETYLASE INHIBITORS FOR INCREASING THE ACTIVITY OF ANTIFUNGAL AGENTS
AU2007234843B2 (en) 2006-04-07 2013-07-11 Methylgene Inc. Inhibitors of histone deacetylase
US20090018142A9 (en) 2006-05-02 2009-01-15 Zhengping Zhuang Use of phosphatases to treat tumors overexpressing N-CoR
TWI449524B (zh) 2006-09-07 2014-08-21 Stemline Therapeutics Inc 以斑螫酸酐（ｃａｎｔｈａｒｉｄｉｎ）及斑螫酸酐類似物進行之癌症治療
WO2008028965A2 (en) 2006-09-08 2008-03-13 Institut Gustave Roussy Inhibitors of protein phosphatase 1, gadd34 and protein phosphatase 1/gadd34 complex, preparation and uses thereof
AU2007321720A1 (en) * 2006-11-15 2008-05-22 Genetic Technologies Limited Compounds, compositions and methods for controlling invertebrate pests
WO2008097561A1 (en) * 2007-02-06 2008-08-14 Lixte Biotechology Holdings, Inc. Oxabicycloheptanes and oxabicycloheptenes, their preparation and use
AU2008284364A1 (en) 2007-08-03 2009-02-12 Lixte Biotechnology, Inc. Use of phosphatases to treat neuroblastomas and medulloblastomas
US8438069B2 (en) 2007-08-23 2013-05-07 Ebay Inc. Methods and systems to facilitate a purchase of an item on a network-based marketplace
CN101854804B (zh) 2007-10-01 2014-07-23 利克斯特生物技术公司 Hdac抑制剂
JP5069091B2 (ja) 2007-12-12 2012-11-07 三菱電機株式会社 監視カメラおよび監視カメラシステム
CA2730148C (en) 2008-08-01 2018-04-03 Lixte Biotechnology, Inc. Neuroprotective agents for the prevention and treatment of neurodegenerative diseases
WO2010147612A1 (en) 2009-06-18 2010-12-23 Lixte Biotechnology, Inc. Methods of modulating cell regulation by inhibiting p53
CA2730428A1 (en) 2008-08-01 2010-02-04 Lixte Biotechnology, Inc. Methods for regulating cell mitosis by inhibiting serine/threonine phosphatase
US8227473B2 (en) * 2008-08-01 2012-07-24 Lixte Biotechnology, Inc. Oxabicycloheptanes and oxabicycloheptenes, their preparation and use
US20120135522A1 (en) 2009-06-18 2012-05-31 Kovach John S Methods of modulating cell regulation by inhibiting p53

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
MATTHEW E HART ET AL: "Modified norcantharidins synthesis, protein phosphatases 1 and 2A inhibition, and anticancer activity", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, PERGAMON, ELSEVIER SCIENCE, GB, vol. 14, no. 8, 19 April 2004 (2004-04-19), pages 1969 - 1973, XP002624048, ISSN: 0960-894X, [retrieved on 20040316], DOI: 10.1016/J.BMCL.2004.01.093 *

Also Published As

Publication number Publication date
EA201170288A1 (ru) 2011-12-30
US20100029484A1 (en) 2010-02-04
MX2011001007A (es) 2011-03-25
CN102333752A (zh) 2012-01-25
US20120264764A1 (en) 2012-10-18
JP2015044816A (ja) 2015-03-12
AU2009277031A1 (en) 2010-02-04
CA2730489C (en) 2017-11-28
WO2010014254A1 (en) 2010-02-04
EA022311B1 (ru) 2015-12-30
HK1151791A1 (en) 2012-02-10
JP2011529883A (ja) 2011-12-15
EP2307344A1 (en) 2011-04-13
CA2730489A1 (en) 2010-02-04
US8541458B2 (en) 2013-09-24
BRPI0911717A2 (pt) 2019-09-24
JP5666443B2 (ja) 2015-02-12
EP2307344A4 (en) 2012-05-02
US8227473B2 (en) 2012-07-24
AU2009277031B2 (en) 2015-01-29

Similar Documents

Publication Publication Date Title
EP2307344B1 (en) Oxabicycloheptanes and oxabicycloheptenes, their preparation and use
US10399993B2 (en) Oxabicycloheptanes and oxabicycloheptenes, their preparation and use
EP2870161B1 (en) Oxabicycloheptanes and oxabicycloheptenes for the treatment of reperfusion injury
CA2718472A1 (en) Use of phosphatases to treat neuroblastomas and medulloblastomas
UA114803C2 (uk) ФОРМИ І СОЛІ ДИГІДРОПІРОЛ[1,2-c]ІМІДАЗОЛІЛЬНОГО ІНГІБІТОРА АЛЬДОСТЕРОНСИНТАЗИ АБО АРОМАТАЗИ
CN113527281B (zh) 杂环化合物及其制备方法和应用
CN117136050A (zh) 用于使用大麻素治疗神经元病症的组合物和方法
JP6627141B2 (ja) ベニバナボロギク抽出物を調製する方法、それにより調製された抽出物、及び抽出物の使用
US12006331B2 (en) Therapeutic compounds and methods
US20230119740A1 (en) Therapeutic compounds and methods
EP3423444B1 (en) Novel types of c-3 substituted kinurenic acid derivatives with improved neuroprotective activity
US20100286219A1 (en) 1, 3-Dihydroimidazoles for Treating Cardiovascular Disorders

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20110124

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO SE SI SK SM TR

AX Request for extension of the european patent

Extension state: AL BA RS

DAX Request for extension of the european patent (deleted)
REG Reference to a national code

Ref country code: HK

Ref legal event code: DE

Ref document number: 1151791

Country of ref document: HK

REG Reference to a national code

Ref country code: DE

Ref legal event code: R079

Ref document number: 602009032569

Country of ref document: DE

Free format text: PREVIOUS MAIN CLASS: C07C0049613000

Ipc: C07D0307000000

A4 Supplementary search report drawn up and despatched

Effective date: 20120402

RIC1 Information provided on ipc code assigned before grant

Ipc: C07D 307/00 20060101AFI20120327BHEP

Ipc: C07D 405/12 20060101ALI20120327BHEP

Ipc: A61K 31/4178 20060101ALI20120327BHEP

Ipc: A61K 31/496 20060101ALI20120327BHEP

17Q First examination report despatched

Effective date: 20130130

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

INTG Intention to grant announced

Effective date: 20150216

GRAS Grant fee paid

Free format text: ORIGINAL CODE: EPIDOSNIGR3

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO SE SI SK SM TR

REG Reference to a national code

Ref country code: GB

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: CH

Ref legal event code: EP

REG Reference to a national code

Ref country code: AT

Ref legal event code: REF

Ref document number: 739170

Country of ref document: AT

Kind code of ref document: T

Effective date: 20150815

REG Reference to a national code

Ref country code: IE

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: DE

Ref legal event code: R096

Ref document number: 602009032569

Country of ref document: DE

REG Reference to a national code

Ref country code: AT

Ref legal event code: MK05

Ref document number: 739170

Country of ref document: AT

Kind code of ref document: T

Effective date: 20150729

REG Reference to a national code

Ref country code: LT

Ref legal event code: MG4D

REG Reference to a national code

Ref country code: NL

Ref legal event code: MP

Effective date: 20150729

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LV

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20150729

Ref country code: LT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20150729

Ref country code: FI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20150729

Ref country code: NO

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20151029

Ref country code: GR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20151030

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: PL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20150729

Ref country code: HR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20150729

Ref country code: AT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20150729

Ref country code: ES

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20150729

Ref country code: SE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20150729

Ref country code: IS

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20151129

Ref country code: PT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20151130

REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: NL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20150729

REG Reference to a national code

Ref country code: IE

Ref legal event code: MM4A

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20150729

Ref country code: MC

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20150729

Ref country code: CZ

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20150729

Ref country code: EE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20150729

Ref country code: LI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20150731

Ref country code: IT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20150729

Ref country code: CH

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20150731

Ref country code: DK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20150729

REG Reference to a national code

Ref country code: DE

Ref legal event code: R097

Ref document number: 602009032569

Country of ref document: DE

REG Reference to a national code

Ref country code: HK

Ref legal event code: GR

Ref document number: 1151791

Country of ref document: HK

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: RO

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20150729

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

26N No opposition filed

Effective date: 20160502

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 8

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20150730

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20150729

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: BE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20150729

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20150729

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SM

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20150729

Ref country code: HU

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT; INVALID AB INITIO

Effective date: 20090730

Ref country code: BG

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20150729

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: CY

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20150729

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 9

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: TR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20150729

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: FR

Payment date: 20170724

Year of fee payment: 9

Ref country code: GB

Payment date: 20170719

Year of fee payment: 9

Ref country code: DE

Payment date: 20170724

Year of fee payment: 9

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LU

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20150730

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20150729

REG Reference to a national code

Ref country code: DE

Ref legal event code: R119

Ref document number: 602009032569

Country of ref document: DE

GBPC Gb: european patent ceased through non-payment of renewal fee

Effective date: 20180730

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: FR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20180731

Ref country code: GB

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20180730

Ref country code: DE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20190201